image of silk fabric and dry skin

A. A. Alrajhi, MD, MPH, FIDSA

Section of Infectious Diseases, Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

ABSTRACT

Cutaneous leishmaniasis is a vector-borne protozoal infection of the skin. Several species of Leishmania cause this disease in the Old World. It is manifested as chronic nodular to ulcerative lesions of the skin, which last for many months and may be disfiguring. They eventually heal leaving a scar. Local care of the lesion and treatment of secondary bacterial infection are essential for healing. Antileishmania therapy is indicated in immunocompromised hosts, patients with progressive, multiple, or critically located lesions. Pentavalent antimony compounds remain the main therapeutic option for all species. They are given intravenously (IV), intramuscularly (IM), or intralesionally. Cryotherapy, and some systemic antifungal agents have been used successfully. Oral azoles are promising new treatments for lesions caused L. major. Several other alternatives and their evidence are also presented.

Key Words: Leishmania, cutaneous leishmaniasis, therapy, review

Cutaneous leishmaniasis of the Old World is wide-spread in the Middle East, Mediterranean littoral, Arabian Peninsula, Africa, Near Asia, Indian Subcontinent and other areas. According to WHO, leishmaniasis is endemic in 66 countries in the Old World, 16 of which are in Europe, and the population at risk is more than 350 million. The infected sand fly transmits promastigotes to humans. The parasites are engulfed by tissue macrophages where they multiply as amastigotes. There are at least five species causing cutaneous leishmaniasis in the Old World (see Table 1). L. major and L. tropica cause the majority of cases. Some species are well known for their visceral involvement, but have also been noted to cause cutaneous lesions. L. donovani causes post kala-azar dermal leishmaniasis.1,2 L. tropica was found to cause visceral disease among American solders serving in the Arabian Peninsula.3 It is apparent that the extent of disease manifestation is a combination of the parasite pathogenesis and the immune host response. A series of complex and not fully understood interactions occur between the species-specific virulence factors and genetically determined cell-mediated immunity. Parasitemacrophage binding triggers a series of cellular and cytokine responses that have been investigated in animal models, but remains less clear in humans.4-7

Parasite SpeciesGeographic distribution
L. majorMiddle East, Indian Subcontinent, northwestern China, Africa
L. tropicaMiddle East, Indian Subcontinent, Mediterranean littoral, western Asiatic areas
L. aethiopicaEast Africa, Yemen
L. infantumMediterranean basin
L. donovaniSudan, East Africa

Table 1: Leishmania species causing cutaneous disease in the Old World.8

Skin lesions develop at the site of inoculation of promastigotes. Therefore, they are rarely seen in covered areas, as in cases of diffuse cutaneous leishmaniasis where lesions may even be nonulcerative papules. The lesion starts as a small nodule that slowly enlarges and then ulcerates. Depending on the age of the lesion and host response, the lesion may be papular, acneform, or nodular with minimal ulceration. The patient may develop a secondary bacterial infection especially on the feet. Small nodules that could ulcerate may appear in the line of the lymphatics draining the area of the primary lesion akin to sporotrichoid presentation. Lesions of leishmaniasis recidivans enlarge slowly while healing in the center, and may last or recur for decades. Diffuse cutaneous leishmaniasis is uncommon. It is related to L. aethiopica in Africa. Mucosal involvement is rare in the Old World. Depending on travel history, differential diagnosis may include fungal or mycobacterial skin infections, cutaneous neoplasms, and sarcoidosis.

Diagnosis is usually suspected in the endemic regions for typical lesions. Confirmation is achieved by obtaining skin scrapings or a biopsy from the lesion edge. A touch preparation using Wright-Giemsa stain reveals the leishmania amastigotes in macrophages or extracellular areas. Leishmania amastigotes are similar in size to Histoplasma capsulatum and can be differentiated by the presence of kinetoplast. The parasite can be grown using one of several culture media. Culturing leishmania will assist in speciating the parasite through isoenzyme analysis9 or monoclonal antibody.10 Serology for cutaneous leishmaniasis is not helpful because of variable antibody elevation.

Treatment

Natural History
Cutaneous leishmaniasis of the Old World eventually heals. The rate of spontaneous healing depends on several factors, including: parasite load and virulence, host immune response, location of the lesion, and the presence or absence of secondary bacterial infection. Lesions caused by L. major heal spontaneously after about 18 weeks.11 L. tropica lesions, on the other hand, typically last for one or two years, but may last for decades. There is no ideal therapy for cutaneous leishmaniasis (topical, effective, inexpensive, and safe). The majority of lesions may best be dealt with using local care and patience. As mucosal leishmaniasis is rare in the Old World, only large, multiple, or diffuse lesions of the face, head and neck need to be considered for therapeutic intervention. Immunocompromised patients should be treated immediately. An important part of therapy for cutaneous leishmaniasis is local care along with antileishmania therapy. Treatment of secondary bacterial infection is essential for healing.

Cryotherapy
Cryotherapy using liquid nitrogen has been used to treat individual lesions. Uncontrolled studies showed enhanced healing either alone or in combination with intralesional antimony.12-14 This modality is labor intensive and not suitable for multiple or complicated lesions. Applying the same principle, nomads of Arabia use cauterization of leishmania skin lesions. It is effective in eliminating the parasites, but the ensuing scar may be larger than that of leishmania.

Intralesional Antimony
This therapy involves injecting antimony compound in the lesion, and requires multiple doses. The doses, number of injections, and intervals vary widely in reported studies. It has been effective alone15 or in combination with cryotherapy.12,14 It is not a practical method in endemic areas because of the high numbers of patients and lesions.

Paromomycin sulphate ointment
An ointment preparation is fairly attractive as therapy for cutaneous leishmaniasis. Paromomycin has been tried for L. major. Results were encouraging at first. However, subsequent randomized trials in four countries for L. major failed to demonstrate the initial success.16-19 Up to 25% of patients who tried this preparation reported side-effects.20

Systemic Therapy

Antimony Compounds
Pentavalent antimonials were used against leishmania as early as 1912.21 Currently, there are two preparations. Sodium stibogluconate (Pentostam®, Wellcome) and
meglumine antimoniate (Glucantime®, Rhone Poulenc) remain the mainstay of therapy for the leishmaniases. For cutaneous leishmaniasis they can be given systematically (IV or IM) or as intralesional injection. Systemic antimonials are associated with many toxicities that limit their use in cutaneous leishmaniasis. They include myalgias, arthralgias, abdominal symptoms, liver enzyme elevation, pancreatitis, bone marrow suppression, neuropathy, cardiac toxicity, and sudden death.22 However, they remain the effective therapy for all species causing cutaneous leishmaniasis in the Old World.

Pentamidine
Pentamidine was tried for leishmania in an attempt to limit side-effects of systemic antimony. The drug had high cure rates in the New World, but was used in only one study in the Old World.23 Eight out of 11 patients (73%) experienced quick healing after three IM injections of 4mg/kg. Further studies are awaited to support its use. For cutaneous leishmaniasis of the Old World, pentamidine can be used as an alternative to an ineffective antimony course.

Amphotericin B
Liposomal amphotericin B lipid formulation is the only US FDA approved agent for visceral leishmaniasis. The experience of amphotericin B for cutaneous leishmaniasis is limited. Because of its adverse effects, which include nephrotoxicity (15%), electrolyte disturbances, fever, rigors and, rarely, hemodynamic collapse, it may only be used as an alternative therapy to antimony. It has been successfully used in antimony resistant post kala azar dermal leishmaniasis.24

Azoles
Azoles inhibit ergosterol biosynthesis of Leishmania parasites.25 Ketoconazole failed to cure any of 14 patients infected with L. tropica who took it for 10 weeks.26 In a randomized study, none of 32 patients receiving ketoconazole healed.19 L. major however, may respond better. In a single arm study in Kuwait, 80% of patients “responded”.27 In a similar study from Saudi Arabia, 85% “responded” to 4-18 weeks of ketoconazole.28 It was also “successful” as a treatment for peace keepers in the Sinai.29 Topical ketoconazole was not as successful.30 The lack of blinding and clear definition of cure make the findings subject to bias.

Because it is better tolerated, itraconazole became another option and has been studied more. Although its in vitro results are better than other azoles31, this agent was not superior to placebo in one randomized study in Iran.32 However, while open label33 or non-comparative studies had a healing rate of around 75%.34,35

The third agent used for cutaneous leishmania is fluconazole. It has the advantage of excellent bioavailability, a favorable adverse events profile, and high skin concentration. A six-week course of 200mg of fluconazole was found to be safe and doubled the chance of healing in a shorter time interval in a randomized, placebocontrolled study in Saudi Arabia.11 The parasites treated were L. major. Other species may not be as responsive.

Other oral agents
Allopurinol was used for leishmania in many areas. Controlled studies in the New World had conflicting results.36,37 Parasites of the Old World may be more susceptible38,39 but randomized studies are lacking. Rifampin has also been used for cutaneous leishmaniasis with promising results. In a placebo-controlled study in India, patients had better chances of healing if they received rifampin.40

TherapyDuration and DoseComments
Systemic antimony20mg/kg for 10-20 daysActive against all species.
Intralesional antimonyVariableNot practical in endemic areas
Pentamidine (IV or IM)4mg/kg alternate days for 3 dosesLimited data
Amphotericin B0.5mg/kg/day for 10-20 daysRarely used because of side effects
Fluconazole200mg/day for six weeksL. major only
Itraconazole200mg twice daily for four weeksL. major only
Ketoconazole600mg/day for four weeksL. major only
Allopurinol300-600mg/day for 4-6 weeksIn combination with an azole. Limited data
CryotherapyVariable number of sessionsLabor intensive
Topical paromomycinTwice daily for 20 daysL. major only

Table 2: Therapies of cutaneous leishmaniasis of the Old World*
* If antileishmania therapy is indicated. The evidence for using many of these therapies is not satisfactory. See text for details.

Conclusion

Cutaneous leishmaniasis of the Old World is endemic in many countries. It poses a risk to the local population, travelers, military personnel, and aid workers. The chronic and sometimes disfiguring lesions eventually heal leaving a scar. Antileishmania therapy is indicated in selected situations, as the disease is self-limiting. When therapy is indicated, antimony compounds are the mainstay of therapy. Other alternatives include parenteral antifungal agents, oral azoles, cryotherapy, and topical paromomycin. Local lesion care and management of secondary bacterial infection are essential. The choice of antileishmania therapy should be based on the patient’s immune status, geographic location, available resources and physician expertise.

References

  1. Addy M, Nandy A. Ten years of kala-azar in west Bengal, Part I. Did postkala-azar dermal leishmaniasis initiate the outbreak in 24-Parganas? Bull
    World Health Organ     70(3):341-6 (1992).
  2. el Hassan AM, Ghalib HW, Zijlstra EE, et al. Post kala-azar dermal leishmaniasis in the Sudan: clinical features, pathology and treatment. Trans
    R Soc Trop Med Hyg     86(3):245-8 (1992).
  3. Magill AJ, Grogl M, Gasser RA, Jr., Sun W, Oster CN. Visceral infection caused by Leishmania tropica in veterans of Operation Desert Storm. N Engl
    J Med     328(19):1383-7 (1993).
  4. Russo DM, Barral-Netto M, Barral A, Reed SG. Human T-cell responses in Leishmania infections. Prog Clin Parasitol 3:119-44 (1993).
  5. Reiner SL, Locksley RM. The regulation of immunity to Leishmania major. Annu Rev Immunol 13:151-77 (1995).
  6. Blackwell JM. Genetic susceptibility to leishmanial infections: studies in mice and man. Parasitology 112(Suppl):S67-74 (1996).
  7. Solbach W, Laskay T. The host response to Leishmania infection. Adv Immunol 74:275-317 (2000).
  8. Lainson R, Show JJ. Evoluation, classification and geographic distribution. In: Peters W, Killick-Kendrick R, eds. The leishmaniases in Biology and
    Medicine    . London: Academic Press; 1987:1-120.
  9. Gardener PJ, Chance ML, Peters W. Biochemical taxonomy of Leishmania. II: Electrophoretic variation of malate dehydrogenase. Ann Trop Med
    Parasitol     68(3):317-25 (1974).
  10. Pratt DM, David JR. Monoclonal antibodies that distinguish between New World species of Leishmania. Nature 291(5816):581-3 (1981).
  11. Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, Faris RM, Maguire JH. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N Engl J Med 346(12):891-5 (2002).
  12. el Darouti MA, al Rubaie SM. Cutaneous leishmaniasis. Treatment with combined cryotherapy and intralesional stibogluconate injection. Int J Dermatol 29(1):56-9 (1990).
  13. Uzun S, Uslular C, Yucel A, Acar MA, Ozpoyraz M, Memisoglu HR. Cutaneous leishmaniasis: evaluation of 3,074 cases in the Cukurova region of Turkey. Br J Dermatol 140(2):347-50 (1999).
  14. Gurei MS, Tatli N, Ozbilge H, et al. Efficacy of cryotherapy and intralesional pentostam in treatment of cutaneous leishmaniasis. J Egypt Soc Parasitol 30(1):169-76 (2000).
  15. Faris RM, Jarallah JS, Khoja TA, al-Yamani MJ. Intralesional treatment of cutaneous leishmaniasis with sodium stibogluconate antimony. Int J Dermatol 32(8):610-2 (1993).
  16. el-Safi SH, Murphy AG, Bryceson AD, Neal RA. A double-blind clinical trial of the treatment of cutaneous leishmaniasis with paromomycin ointment. Trans R Soc Trop Med Hyg 84(5):690-1 (1990).
  17. Ben Salah A, Zakraoui H, Zaatour A, et al. Arandomized, placebo-controlled trial in Tunisia treating cutaneous leishmaniasis with paromomycin ointment. Am J Trop Med Hyg 53(2):162-6 (1995).
  18. Asilian A, Jalayer T, Whitworth JA, Ghasemi RL, Nilforooshzadeh M, Olliaro P. A randomized, placebo-controlled trial of a two-week regimen of aminosidine (paromomycin) ointment for treatment of cutaneous leishmaniasis in Iran. Am J Trop Med Hyg 53(6):648-51 (1995).
  19. O, Baydar I. A randomized clinical trial of topical paromomycin versus oral ketoconazole for treating cutaneous leishmaniasis in Turkey. Int J Dermatol 36(1):61-3 (1997).
  20. Soto J, Hernandez N, Mejia H, Grogl M, Berman J. Successful treatment of New World cutaneous leishmaniasis with a combination of topical paromomycin/methylbenzethonium chloride and injectable meglumine antimonate. Clin Infect Dis 20(1):47-51 (1995).
  21. Berman JD. Chemotherapy for leishmaniasis: biochemical mechanisms, clinical efficacy, and future strategies. Rev Infect Dis 10(3):560-86 (1988).
  22. Herwaldt BL, Berman JD. Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 46(3):296-306 (1992).
  23. Hellier I, Dereure O, Tournillac I, et al. Treatment of Old World cutaneous leishmaniasis by pentamidine isethionate. An open study of 11 patients. Dermatology 200(2):120-3 (2000).
  24. Hashim FA, Khalil EA, Ismail A, el Hassan AM. Apparently successful treatment of two cases of post kala-azar dermal leishmaniasis with liposomal
    amphotericin B. Trans R Soc Trop Med Hyg 89(4):440 (1995).
  25. Hart DT, Lauwers WJ, Willemsens G, Vanden Bossche H, Opperdoes FR. Perturbation of sterol biosynthesis by itraconazole and ketoconazole in Leishmania mexicana mexicana infected macrophages. Mol Biochem Parasitol 33(2):123-34 (1989).
  26. Singh S, Singh R, Sundar S. Failure of ketoconazole treatment in cutaneous leishmaniasis. Int J Dermatol 34(2):120-1 (1995).
  27. Alsaleh QA, Dvorak R, Nanda A. Ketoconazole in the treatment of cutaneous leishmaniasis in Kuwait. Int J Dermatol 34(7):495-7 (1995).
  28. Kubba R, Al-Gindan Y, El-Hassan AM, Omer AH. Ketoconazole in cutaneous leishmaniasis: results of a pilot study. Saudi Med J 7(6):596-604 (1986).
  29. Norton SA, Frankenburg S, Klaus SN. Cutaneous leishmaniasis acquired during military service in the Middle East. Arch Dermatol 128(1):83-7 (1992).
  30. Abahusein A, Larbi EB, al-Khawajah A, al-Gindan Y, Jain S. Evaluation of topical ketoconazole in cutaneous leishmaniasis. East Afr Med J 69(1):14-7 (1992).
  31. Beach DH, Goad LJ, Holz GG, Jr. Effects of antimycotic azoles on growth and sterol biosynthesis of Leishmania promastigotes. Mol Biochem Parasitol 31(2):149-62 (1988).
  32. Momeni AZ, Jalayer T, Emamjomeh M, et al. Treatment of cutaneous leishmaniasis with itraconazole. Randomized double-blind study. Arch Dermatol 132(7):784-6 (1996).
  33. al-Fouzan AS, al Saleh QA, Najem NM, Rostom AI. Cutaneous leishmaniasis in Kuwait. Clinical experience with itraconazole. Int J Dermatol 30(7):519-21 (1991).
  34. Dogra J, Aneja N, Lal BB, Mishra SN. Cutaneous leishmaniasis in India. Clinical experience with itraconazole (R51 211 Janssen). Int J Dermatol 29(9):661-2 (1990).
  35. Van den Enden E, Van Gompel A, Stevens A, et al. Treatment of cutaneous leishmaniasis with oral itraconazole. Int J Dermatol 33(4):285-6 (1994).
  36. Martinez S, Marr JJ. Allopurinol in the treatment of American cutaneous leishmaniasis. N Engl J Med 326(11):741-4 (1992).
  37. Velez I, Agudelo S, Hendrickx E, et al. Inefficacy of allopurinol as monotherapy for Colombian cutaneous leishmaniasis. A randomized, controlled trial. Ann Intern Med 126(3):232-6 (1997).
  38. Ghanem BM, el-Shazly AM, Fawzy M, Arafa MA, Morsy TA. Allopurinol in the treatment of zoonotic cutaneous leishmaniasis. J Egypt Soc Parasitol 26(3):619-28 (1996).
  39. Momeni AZ, Aminjavaheri M. Treatment of recurrent cutaneous Leishmaniasis. Int J Dermatol 34(2):129-33 (1995).
  40. Kochar DK, Aseri S, Sharma BV, Bumb RA, Mehta RD, Purohit SK. The role of rifampicin in the management of cutaneous leishmaniasis. QJM 93(11):733-7 (2000).
STL Volume 8 Number 2

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